Takamura T, Kato I, Kimura N, Nakazawa T, Yonekura H, Takasawa S, Okamoto H
Department of Biochemistry, Tohoku University School of Medicine, Sendai 980-77, Miyagi, Japan.
J Biol Chem. 1998 Jan 30;273(5):2493-6. doi: 10.1074/jbc.273.5.2493.
We generated transgenic mice carrying the mouse type 2 nitric-oxide synthase (NOS2) cDNA under the control of the insulin promoter. Western and immunohistochemical analyses revealed that NOS2 was expressed abundantly in transgenic islets but not in control islets. When islets were isolated and cultured, high levels of nitrite were released from the transgenic islets. In transgenic mice, the beta cell mass was markedly reduced without the infiltration of macrophages or lymphocytes, and extensive DNA strand breaks were detected in the islets by in situ nick translation. All the transgenic mice developed hypoinsulinemic diabetes by 4 weeks of age, and treatment with an inhibitor of NOS2, aminoguanidine (200 mg/kg body weight every 12 h), prevented or delayed the development of diabetes. The present study shows that the production of nitric oxide by beta cell NOS2 plays an essential role in the beta cell degeneration.
我们构建了在胰岛素启动子控制下携带小鼠2型一氧化氮合酶（NOS2）cDNA的转基因小鼠。蛋白质免疫印迹和免疫组织化学分析显示，NOS2在转基因胰岛中大量表达，而在对照胰岛中不表达。分离并培养胰岛时，转基因胰岛释放出高水平的亚硝酸盐。在转基因小鼠中，β细胞量显著减少，没有巨噬细胞或淋巴细胞浸润，并且通过原位缺口平移在胰岛中检测到广泛的DNA链断裂。所有转基因小鼠在4周龄时均出现低胰岛素血症性糖尿病，用NOS2抑制剂氨基胍（每12小时200mg/kg体重）治疗可预防或延缓糖尿病的发生。本研究表明，β细胞NOS2产生一氧化氮在β细胞变性中起重要作用。
